Kainate receptors (KARs) are a family of ionotropic glutamate receptors whose primary function is to help maintain the critical balance between excitatory and inhibitory processes in the central nervous system. Because KARs are primarily serve modulatory roles, rather than underlying integral components of basic excitatory transmission, they may prove more approachable drug targets than AMPA or NMDA receptors. KARs subserve their modulatory role in part by virtue of a remarkably heterogeneous distribution in different neuronal populations. The neuron-specific cellular mechanisms that direct polarized distribution and synaptic (or extrasynaptic) targeting of KARs remain largely unknown. Our long-term objective is to elucidate the molecular processes that control constitutive and regulated KAR localization in neurons. We have discovered that Epb4.1 proteins alter neuronal KAR localization and function through interactions with conserved regions of receptor subunit carboxy-terminal domains. In this project, we will identify the site(s) and subunit specificity of this association, how 4.1 proteins control localization of KARs in neurons, and determine how posttranslational modifications such as palmitoylation and phosphorylation modulate the interaction between 4.1 proteins and KAR subunits. Understanding the molecular and cellular bases for these processes is an important objective, because KARs represent new therapeutic targets for a number of neuropathologies, including chronic pain, anxiety and epilepsy. PUBLIC HEALTH RELEVANCE: Kainate receptors are multifunctional proteins that influence the balance between excitatory and inhibitory systems in the mammalian brain. The cellular mechanisms that control their synthesis and localization in the brain are poorly understood, but these processes are critical for the normal functioning of the receptor proteins. In this grant, we will elucidate the role of a set of intracellular proteins in moving kainate receptors to their site(s) of functional activity in neurons.